Compounds comprising structures similar to the 8-aminoalkoxy-xanthine derivatives and their salts as described herein are known and have also been described in the art for the treatment of hyperlipidemia and diabetes. Basic substituted caffeine derivatives of similar structure are described in U.S. Pat. No. 2,688,618. WO92/05175 describes compounds of similar structure for the treatment of allergies.
The 8-aminoalkoxy-xanthine derivative compounds of the present invention are highly effective in the therapeutic modulation of lipid and/or carbohydrate metabolism and are therefore useful in the prevention and/or treatment of diseases such as type-2 diabetes and atherosclerosis, and the many other diverse cardiovascular, among others, manifestations arising therefrom. The utilization of an oxadiazolone feature as inhibitors of factor Xa were disclosed in DE 101 12 768 A1 and oxodiazolones have also been described as oral hypoglycemic agents in WO 96/13264.
The enzyme dipeptidyl peptidase-IV (DPP-IV) inactivates a variety of bioactive peptides, including glucagon-like peptide-1 (GLP-1) and growth hormone releasing hormone (GHRH). Inhibiting DPP-IV in order to increase circulating GLP-1 is of interest as a treatment for Type II diabetes. Inactivation of DPP-IV may also increase circulating GHRH, potentially enhancing growth in domestic animals
One such substituted 8-aminoalkoxy-xanthine derivative compound similar to those of the present invention has been shown to act on the central nervous system (J. Med. Chem. (1966), 9 500-6). Inhibition of DPP-IV increases the circulating half-life of the incretin hormones GLP-1 and GIP, improving glucose tolerance in Type II diabetics. Complete inhibition of DPP-IV does not appear to be necessary as 2- to 3-fold increases in plasma concentrations of GLP-1 have been achieved in mice with inactivation of 84% to 96% of plasma DPP-IV. Thus, there has been much interest in developing DPP-IV inhibitors for the treatment of Type II diabetes and other metabolic disorders.
DPP-IV exists as both a membrane-spanning form present in cells throughout the body and a soluble circulating form. Both forms of DPP-IV have identical enzymatic activity and cleave a wide range of bioactive peptides in vitro, including hormones, neuropeptides, and chemokines. One potential regulatory role of DPP-IV is the inactivation of GHRH through cleavage of the active form, GHRH(1-44)-NH2, to the N-terminally shortened inactive form, GHRH(3-44)-NH2, While trypsin-like degradation of GHRH also occurs, in vitro studies using GHRH analogs designed to resist cleavage at the N-terminus have demonstrated that the primary degradation of GHRH is via DPP-IV. Substitution of Ala2 with Dali prevents DPP-IV proteolysis and administration of this analog increases GH release in swine up to 2-fold. The His1, Val2 analog of GHRH is also not degraded by DPP-IV in vitro, and it demonstrates increased plasma stability over native GHRH. GHRH analogs containing the His1, Val2 substitutions were 5.4- to 12.5-fold more potent than native GHRH in release of GH in swine. Thus, inhibition of DPP-IV in vivo may increase endogenous concentrations of GHRH and enhance GH secretion.
Compounds of similar structure have been described in the prior art such as the bicyclic xanthine derivatives and their use as DDPIV inhibitors described in U.S. Pat. No. 7,074,798 to Yoshikawa et. al. which is hereby incorporated by reference
The present invention involves 8-aminoalkoxy-xanthine derivative compounds of formula I